The present invention is concerned with amino acid derivatives and a process for their manufacture. The invention is also concerned with pharmaceutical preparations containing these derivatives and with the use of these derivatives as medicaments, especially antiviral medicaments.
The antiviral medicaments provided in accordance with the present invention are amino acid derivatives represented by the general formula 
wherein
E represents xe2x80x94CHO or xe2x80x94B(OH)2;
R1 represents lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower-alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl, lower alkenyl or lower alkynyl;
R2 represents R2a or R2b;
R2a represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower alkyl;
R2b represents aryl-lower alkoxy-aryl-lower alkyl or heteroaryl-lower alkyl;
R3 represents hydrogen or lower alkyl; or
R2 and R3 together represent di- or trimethylene optionally substituted by hydroxy;
R4 represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl or lower cycloalkyl;
R5 represents R5a or R5b;
R5a represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl or lower cycloalkyl;
R5b represents lower cycloalkyl-lower alkyl;
R6 represents hydrogen or lower alkyl;
R7 represents R7a or R7b;
R7a represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl;
R7b represents aryl-lower alkylthio-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, aryl-lower alkylcarbonyl-lower alkyl, nitroguanidino-lower alkyl, arylsulfonyl-guanidino-lower alkyl, lower alkylsulfonyl-lower alkyl, acetamidomethylthio-lower alkyl, aryl or heteroaryl-lower alkyl;
R8 represents R8a or R8b;
R8a represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or aryl-lower alkyl;
R8b represents mercapto-lower alkyl, lower alkylsulfonyl-lower alkyl, aryl-lower alkoxy-lower alkyl or aryl-heteroaryl-lower alkyl;
R9 represents R9a or R9b;
R9a represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, lower alkylsulfonyl, arylsulfonyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl; and
R9b represents aryl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl, arylaminocarbonyl-lower alkylcarbonyl, heteroarylthio-lower alkylcarbonyl, heteroarylcarbonyl, hydroxyfluorenylcarbonyl, heteroarylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkylcarbonyl, arylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkylcarbonyl, arylcarbonylamino-lower alkylcarbonyl, lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonyl-lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonylamino-lower alkylcarbonyl, heterocyclylcarbonyl, lower alkylcarbonyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylcarbonyl, aryloxy-lower alkylcarbonyl, lower alkynylcarbonyl or lower cycloalkylcarbonyl;
provided that R2, R5, R7, R8 and R9 do not simultaneously represent R2a, R5a, R7a, R8a and R9a, respectively;
and salts of acidic compounds of formula I with bases. The compounds of formula I inhibit proteinases of viral origin and can be used in the treatment of viral infections, especially viral infections caused by hepatitis C, hepatitis G and human GB viruses.
The antiviral medicaments provided in accordance with the present invention are amino acid derivatives represented by the general formula 
wherein
E represents xe2x80x94CHO or xe2x80x94B(OH)2;
R1 is selected from the group consisting of lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower-alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl, lower alkenyl and lower alkynyl;
R2 represents R2a or R2b;
R2a is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, aminocarbonyl-lower alkyl and lower cycloalkyl-lower alkyl;
R2b represents aryl-lower alkoxy-aryl-lower alkyl or heteroaryl-lower alkyl;
R3 represents hydrogen or lower alkyl; or
R2 and R3 together represent di-or trimethylene optionally substituted by hydroxy;
R4 is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower cyclo-alkyl-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl and lower cycloalkyl;
R5 represents R5a or R5b;
R5a is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl and lower cycloalkyl;
R5b represents lower cycloalkyl-lower alkyl;
R6 represents hydrogen or lower alkyl;
R7 represents R7a or R7b;
R7a is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower cycloalkyl-lower alkyl and lower cycloalkyl;
R7b is selected from the group consisting of aryl-lower alkylthio-lower alkyl, aryl-lower alkoxy-aryl-lower alkyl, aryl-lower alkoxycarbonyl-lower alkyl, aryl-lower alkylcarbonyl-lower alkyl, nitroguanidino-lower alkyl, arylsulfonyl-guanidino-lower alkyl, lower alkylsulfonyl-lower alkyl, acetamidomethylthio-lower alkyl, aryl and heteroaryl-lower alkyl;
R8 represents R8a or R8b;
R8a is selected from the group consisting of lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl and aryl-lower alkyl;
R8b is selected from the group consisting of mercapto-lower alkyl, lower alkylsulfonyl-lower alkyl, aryl-lower alkoxy-lower alkyl and aryl-heteroaryl-lower alkyl;
R9 represents R9a or R9b;
R9a is selected from the group consisting of lower alkylcarbonyl, carboxy-lower alkyl-carbonyl, arylcarbonyl, lower alkylsulfonyl, arylsulfonyl, lower alkoxycarbonyl and aryl-lower alkoxycarbonyl; and
R9b is selected from the group consisting of aryl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl, arylaminocarbonyl-lower alkylcarbonyl, heteroarylthio-lower alkylcarbonyl, heteroaryl-carbonyl, hydroxyfluorenylcarbonyl, heteroarylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkylcarbonyl, arylcarbonyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkylcarbonyl, arylcarbonylamino-lower alkylcarbonyl, lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonyl-lower cycloalkyl-lower alkylcarbonyl, lower alkylcarbonylamino-lower alkylcarbonyl, heterocyclylcarbonyl, lower alkylcarbonyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylcarbonyl, aryloxy-lower alkyl-carbonyl, lower alkynylcarbonyl and lower cycloalkylcarbonyl;
with the proviso that R2, R5, R7, R8 and R9 do not simultaneously represent R2a, R5a, R7a, R8a and R9a, respectively;
and salts of acidic compounds of formula I with bases.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight-chain or branched-chain alkyl group containing 1-7, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, neopentyl, preferably 1-4, carbon atoms, and the like. The term xe2x80x9clower alkenylxe2x80x9d denotes a straight-chain or branched-chain alkenyl group containing 2-7 carbon atoms, e.g. vinyl, allyl, n-propenyl, n-butenyl and the like, and the term xe2x80x9clower alkynylxe2x80x9d denotes a straight-chain or branched-chain alkynyl group containing 2-7 carbon atoms, e.g. propargyl, 5-hexynyl,6-heptynyl and the like. The term xe2x80x9ccycloalkylxe2x80x9d denotes a cycloalkyl group containing 3-7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl group as defined hereinbefore, which is bonded via an oxygen atom, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert.butoxy and the like. The term xe2x80x9carylxe2x80x9d denotes a monocyclic or polycyclic aromatic group, e.g. phenyl, naphthyl or the like, which may be unsubstituted or substituted by one or more substituents selected from e.g. lower alkyl, lower alkoxy, halo, i.e. fluoro, chloro, bromo or iodo, halo-lower alkyl, e.g. trifluoromethyl, hydroxy, sulfamoyl and acetamido. The term xe2x80x9cheteroarylxe2x80x9d denotes a 5- or 6-membered aromatic heterocyclic group which contains N, O or S as the hetero atom(s) and which is optionally fused with benzene or optionally substituted in the same manner as the aryl group defined hereinbefore. Furyl, thienyl, pyridyl, pyrimidinyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, indolyl and the like are examples of heteroaryl groups. The term xe2x80x9cheterocyclylxe2x80x9d denotes a saturated or partly unsaturated, 5- or 6-membered heterocyclic group which contains N, 0 or S as the hetero atom(s) and which is optionally fused with benzene or optionally substituted in the same manner as the aryl group defined hereinbefore or by oxo or thioxo. Examples of heterocyclyl groups are thiazolidinyl, 1,2,3,4-tetrahydropyrimidinyl, hexahydropyrimidinyl, 5,6-dihydropyranyl and the like. It will be appreciated that the aforementioned definitions apply to the respective groups when they stand alone or are combined with a further group or groups.
The following sub-groups of compounds of those represented by formula I are preferred: 
wherein E, R1, R2a, 2b, R3, R4, R5a, R6, R7a, R7b, R8a, R8b, R9a and R9b have the significance given earlier.
In formulae I and IA to IF R1 preferably represents lower alkyl or halo-lower alkyl, especially fluoro-lower alkyl. R2a preferably represents lower alkyl. R3 preferably represents hydrogen. R4 preferably represents lower alkyl. R5a preferably represents aryl-lower alkyl. R6 preferably represents hydrogen. R7a preferably is a member of the group consisting of lower alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower cycloalkyl-lower alkyl and lower cycloalkyl. R7b preferably preferably is a member of the group consisting of nitroguanidino-lower alkyl, acetamidomethylthio-lower alkyl and lower alkylsulfonyl-lower alkyl. R8a preferably is a member of the group consisting of carboxy-lower alkyl, hydroxy-lower alkyl and aryl-lower alkyl. R8b preferably represents aryl-heteroaryl-lower alkyl. R9a preferably is a member of the group consisting of lower alkylcarbonyl, carboxy-lower alkylcarbonyl and arylcarbonyl. R9b preferably preferably is a member of the group consisting of heteroarylcarbonyl, hydroxyfluorenylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl-lower alkylcarbonyl, heteroaryl-lower alkylcarbonyl and aryl-lower alkylcarbonyl.
Examples of preferred compounds falling within formulae IA to IF are:
Formula IA:
2(RS)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-O-benzyl-L-tyrosyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-O-(2,6-dichlorobenzyl)-L-tyrosyl]amino]-4,4,4-trifluorobutyraldehyde; and
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-2-(3-thienyl)-L-alanyl]amino]-4,4,4-trifluorobutyraldehyde.
Formula IB:
2(RS)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-L-xcex1-aspartyl]-O-benzyl-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-N6-nitro-L-arginyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-S-(acetamidomethyl)-L-cysteinyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-S-benzyl-L-cysteinyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-3-(3-thenyl)-D-alanyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-D-tryptophyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-O-benzyl-D-tyrosyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-S-(4-methoxybenzyl)-D-cysteinyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-xcex1-aspartyl]-O-benzyl-D-threonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(4-chloro-3-sulphamoylbenzoyl)-L-seryl)]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(4-acetamidobenzoyl)-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-hydroxy-4,5-dimethoxybenzoyl)-L-seryl)]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(2-ethylbutyryl)-L-seryl)]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
1(RS)-[[N-[N-[N-[N-(N-acetyl-L-xcex1-aspartyl)-S,S-dioxo-L-methionyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid (SEQ ID NO:3); and
1(RS)-[[N-[N-[N-[N-(N-acetyl-L-xcex1-aspartyl)-S-[(acetamido)methyl]-L-cysteinyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-propylboronic acid (SEQ ID NO. 4).
Formula IC:
1(RS)-[[N-[N-[N-[N-[N-Acetyl-1-(2,4-dinitrophenyl)-L-histidyl]-O-benzyl-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N2-[N-acetyl-1-(2,4-dinitrophenyl)-L-histidyl]-O-benzyl-N6-(p-toluenesulfonyl)-L-arginyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N-[N-acetyl-1-(2,4-dinitrophenyl)-L-histidyl]-O-bebenzyl-D-tyrosyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N-[N-acetyl-1-(2,4-dinitrophenyl)-L-histidyl]-4-nitro-D-phenylalanyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N-[N-acetyl-1-(2,4-dinitrophenyl)-L-histidyl]-O-bebenzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N-[N-acetyl-1-(2,4-dinitrophenyl)-L-histidyl]-D-2-phenylglycyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N2-[N-acetyl-O-benzyl-L-seryl]-nitro-L-arginyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N-[N-acetyl-O-benzyl-L-seryl]-S-benzyl-L-cysteinyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N-[N-acetyl-O-benzyl-L-seryl]-D-tryptophyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid;
1(RS)-[[N-[N-[N-[N2-(N-acetyl-S,S-dioxo-L-methionyl]-N6-nitro-L-arginyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid; and
2(RS)-[[N-[N-[N-[N2-(N-acetyl-L-tyrosyl)-N6-nitro-L-arginyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:5).
Formula ID:
2(RS)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-S,S-dioxo-L-methionyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-S,S-dioxo-S-methyl-L-cysteinyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-1-(2,4-dinitrophenyl)-L-histidyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS )-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-cysteinyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde; and
1(RS)-[[N-[N-[N-[N-[N-acetyl-1-(2,4-dinitrophenyl)-L-histidyl]-L-2-cyclohexylglycyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]propylboronic acid.
Formula IE:
2(RS)-[[N-[N-[N-[N-[N-[4-xcex14-Methylphenyl)butyryl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:6);
2(RS)-[[N-[N-[N-[N-[N-[3-(4-methylbenzoyl)propionyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:7);
2(RS)-[[N-[N-[N-[N-[N-[2-[2-(2-methoxyethoxy)ethoxyacetyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:8);
2(RS)-[[N-[N-[N-[N-[N-[2-(4-oxo-2-thioxo-3-thiazolidinyl)acetyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]-4,4,4-trifluorobutyraldehyde(SEQ ID NO:9);
2(RS)-[[N-[N-[N-[N-[N-[3-(2-methyl-4-nitro-1-imidazolyl)propionyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:10);
2(RS)-[[N-[N-[N-[N-[N-(5-hexynoyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:11);
2(RS)-[[N-[N-[N-[N-[N-[(6-quinolyl)carbonyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl -2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:12);
2(RS)-[[N-[N-[N-[N-[N-[(6-oxo-3-pyranyl)carbonyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:13);
2(RS)-[[N-[N-[N-[N-[N-[2-(1,3-benzodioxol-5-yl)acetyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:14);
2(RS)-[[N-[N-[N-[N-[N-[(5,6-dihydro-6,6-dimethyl-4-oxo-4H-pyran-2-yl)carbonyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:15);
2(RS)-[[N-[N-[N-[N-[N-[2-(2-naphthyl)acetyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:16);
2(RS)-[[N-[N-[N-[N-[N-(3-benzamidopropionyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:17);
2(RS)-[[N-[N-[N-[N-[N-[(1,2,3,4-tetrahydro-2,4-dioxo-5-pyrimid-inyl)carbonyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:18);
2(RS)-[[N-[N-[N-[N-[N-(3-methyl-2-thenoyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:19);
2(RS)-[[N-[N-[N-[N-N-(2-cyclohexylacetyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:20);
2(RS)-[[N-[N-[N-[N-[N-[2(RS)-(4-nitrophenyl)propionyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde (SEQ ID NO:21)
1(RS)-[[N-[N-[N-[N-[N-[(6-oxo-6H-pyran-3-yl)carbonyl]-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]propylboronic acid (SEQ ID NO:22
1(RS)-[[N-[N-[N-[N-[N-(4-acetamidobutyryl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid (SEQ ID NO:23); and
1(RS)-[[N-[N-[N-[N-[N-(2-acetoxyacetyl)-L-xcex1-aspartyl]-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid (SEQ ID NO:24).
Formula IF:
2(RS)-[[N-[N-[N-[N-[N-[2-(2,4,6-Trimethylphenyl)acetyl]-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[(1H-benzotriazol-5-yl)carbonyl-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[4-(phenylcarbamoyl)-butyryl]-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[2-[(4,6-dimethyl-2-pyrimidinyl)thio]acetyl]-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[(2-chloro-3-pyridyl)carbonyl]-L-seryl]-O-bebenzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[(9-hydroxy-9-fluorenyl)carbonyl-L-seryl]-O-bebenzyl- D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[(2-furoyl)-L-seryl]-O-bebenzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[2(RS)-(4-nitrophenyl)propionyl]-L-seryl]-O-bebenzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-[2-(2-chlorophenyl)acetyl]-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde;
2(RS)-[[N-[N-[N-[N-[N-(2-ethoxyacetyl)-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde; and
2(RS)-[[N-[N-[N-[N-[N-[(3-fluoro-4-hydroxyphenyl)acetyl]-L-seryl]-O-bebenzyl-D-seryl -2-methyl-L-phenylalanyl -3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde.
According to the process provided by the present invention, the compounds of formula I hereinbefore and salts of acidic compounds of formula I with bases are manufactured in accordance with one of the following:
a) for the manufacture of a compound of formula I in which E represents CHO, deacetalizing and, where required, deprotecting an acetal of the general formula 
wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 have the significance given earlier, provided that any carboxy, hydroxy or aminocarbonyl group(s) present is/are in protected form, and R10 and R11 each represent lower alkyl;
b) for the manufacture of a compound of formula I in which E represents B(OH)2, ring opening and, where required, deprotecting a substituted dioxaborolane of the general formula 
wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 have the significance given earlier, provided that any carboxy, hydroxy or aminocarbonyl group(s) present may be in protected form, and Q represents a group of the formula 
wherein R12, R13, R14, R15, R16 and R17 each represent hydrogen or lower alkyl.
If desired, an acidic compound of formula I may be converted into a salt with a base.
Protected carboxy, hydroxy and aminocarbonyl groups which are present in the acetal starting materials of formula II and which may be present in the substituted dioxaborolane starting materials of formula III are protected with a conventional protecting group known from peptide chemistry. In particular, R2, R4, R7, R8 or R9 can preferably represent tert-butoxycarbonyl-lower alkyl as protected carboxy, R2, R4, R5, R7 R8 or R9 can preferably represent lower alkyl O-tert.butyl ether as protected hydroxy and R2 can preferably represent tritylamino-carbonyl-lower alkyl as protected aminocarbonyl-lower alkyl.
The deacetalization of an acetal of formula II, preferably one in which R10 and R11 each represent methyl, according to embodiment a) of the inventive process can be carried out in a manner known per se. It is conveniently effected using trifluoroacetic acid or an equivalent strong acid in the presence of an inert organic solvent, such as a halogenated aliphatic hydrocarbon, e.g. dichloromethane, and in the presence of water. Suitably, the deacetalization is carried out at about room temperature. When protected carboxy, hydroxy or aminocarbonyl groups are present in the acetal starting material, these are converted into free carboxy, hydroxy or aminocarbonyl groups under the conditions of the deacetalization.
According to a variant of embodiment a) of the inventive process, an acetal starting material of formula II is bonded to a solid phase peptide synthesis resin. In this case, cleavage from the resin takes place under the conditions used for the deacetalization.
The ring opening of a substituted dioxaborolane of formula III in which Q represents a group of formula (a), preferably one in which R12, R13, R14 and R15 each represent methyl, according to embodiment b) of the inventive process can also be carried out using conventional methods. Conveniently, the ring opening is carried out using trifluoroacetic acid or an equivalent strong acid in an inert organic solvent, e.g. a halogenated aliphatic hydrocarbon such as dichloromethane, and optionally in the presence of water. Suitably, the ring opening is carried out at about room temperature. When protected carboxy, hydroxy or aminocarbonyl groups are present in the substituted dioxaborolane starting material, these are converted into free form under the conditions of the ring opening.
The ring opening of a substituted dioxaborolane of formula III in which Q represents a group of formula (b), especially one in which one of R16 and R17 represents hydrogen and the other represents methyl, according to embodiment b) of the process in accordance with the invention can be carried out in a conventional manner. Conveniently, the ring opening is carried out using a periodate, especially an alkali metal periodate, especially sodium periodate in a buffered aqueous-organic medium, suitably at about room temperature. Advantageously, the medium consists of a mixture of an inert water-miscible organic solvent, e.g. acetone, and aqueous ammonium acetate. Any protected carboxy, hydroxy or aminocarbonyl group(s) present in the substituted dioxaborolane starting material are deprotected in a manner known per se, e.g. by treatment with trifluoroacetic acid, prior to the ring opening.
According to a variant of embodiment b) of the process according to the invention, a substituted dioxaborolane of formula III in which Q represents a group of formula (a) is bonded to a solid phase synthesis resin. The bonding is typically through an alkyl group R12, R13, R14 or R15 linked to the resin via an amide bridge. Cleavage from the resin takes place under the conditions used in embodiment b) of the process.
Acidic compounds of formula I can be converted into salts with bases, e.g. alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts with organic bases, e.g. salts with amines such as N-ethylpiperidine, procaine or dibenzylamine, or salts with basic amino acids such as salts with arginine or lysine. The formation and isolation of such salts can be carried out according to known methods.
The acetal starting materials of formula II are novel and are to be considered within the scope of the present invention. They can be prepared, for example, by initially reducing a hydroxamate of the general formula 
wherein R1, R10 and R11 have the significance given earlier and Q1 represents an amino protecting group, e.g. tert.butoxycarbonyl, with an alkali metal aluminium hydride, e.g. lithium aluminium hydride, treating the product with methanolic hydrochloric acid to give the hydrochloride salt of a compound of the general formula 
wherein R1, R10 and R11 have the significance given earlier, and subsequently either subjecting this to sequential coupling with respective amino acids or subjecting a fragment obtained during such a sequential coupling to further coupling with a peptide derivative of appropriate length. Alternatively, a compound of formula V can be coupled with a suitable pentapeptide.
The aforementioned coupling reactions can be carried out in a manner known per se in peptide chemistry, conveniently using the respective amino acid or di, tri-, tetra- or pentapeptide appropriately protected as described above and also at any amino group present by Fmoc [(9-fluorenyl)methoxycarbonyl] in the presence of hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-methylmorpholine and in an inert organic solvent, e.g. a halogenated hydrocarbon such as dichloromethane.
The hydroxamates of formula IV required for the preparation of the acetal starting materials of formula II are known compounds or analogues of known compounds which can be prepared in an analogous manner to the known compounds.
The acetal starting materials of formula II can also be synthesized from a compound of formula V on a solid phase peptide synthesis resin. This procedure is known and is described in detail in Handbook from Fourth International Symposium on Solid Phase Synthesis and Combinatorial Chemical Libraries, Edinburgh, 1995.
The substituted dioxaborolanes of formula III used as starting materials in embodiment b) of the process according to the invention are novel are to be considered within the scope of the present invention. They can be prepared, for example, as illustrated in Scheme A hereinafter in which R1 and Q have the significance given earlier: 
Having regard to Scheme A, in step a) a compound of formula VI is reacted with an alkali metal bis[tri(lower alkyl)silyl]amide, e.g. lithium bis(trimethylsilyl)amide, in an inert organic solvent such as an ether, e.g. diethyl ether or tetrahydrofuran, and then treated with a strong acid, e.g. trifluoroacetic acid, to give a compound of formula VII.
In step b) a compound of formula VII is converted into a compound of formula III either by coupling with a pentapeptide, by sequential coupling with respective amino acids or by coupling a fragment obtained during the sequential coupling with a peptide derivative of the desired length, with the amino acid or peptide used being appropriately protected as described above and also at any amino group present by Fmoc. These coupling reactions can be carried out in a manner known per se in peptide chemistry, for example using the amino acid or peptide in the form of a mixed anhydride formed e.g. with a lower alkyl haloformate such as isobutyl chloroformate and carrying out the coupling in the presence of a suitable base, e.g. a tertiary organic base such as N-methylmorpholine.
Substituted dioxoborolanes of formula III obtained by the foregoing coupling and which carry a protecting group on the substituent at R2, R4, R5, R7, R8 or R9 can be selectively deprotected in a conventional manner, e.g. using trifluoroacetic acid, to the corresponding compounds which carry a free carboxy, hydroxy or aminocarbonyl group on the respective substituent, while retaining the protected boronic acid moiety denoted by Q. These selectively deprotected compounds are also active as inhibitors of proteinases of viral origin and can be used in the treatment of viral infections in the same manner as the compounds of formula I.
Compounds of formula VI can be prepared, for example, from a compound represented by the general formula
Cl2CHxe2x80x94Qxe2x80x83xe2x80x83(VIII)
wherein Q has the significance given earlier, which is a known compound or an analogue of a known compound, by reaction with a compound of the formula R1-MgHal, wherein R1 has the significance given earlier and Hal represents halogen, preferably bromine. The reaction is carried out under the conventional conditions of a Grignard reaction, for example in an inert organic solvent such as an ether, e.g. diethyl ether or tetrahydrofuran. When Q represents a group of formula (b), the reaction is carried out in the presence of zinc chloride.
A compound of formula VI in which R1 represents bromo-lower alkyl or fluoro-lower alkyl and Q represents a group of formula (a) can be prepared, for example, by hydroborating a bromo-or fluoro-lower alkene, e.g. 3-bromopropene or 3-fluoropropene, reacting the hydroboration product with a diol of the formula R12R13C(OH)xe2x80x94C(OH)R14R15, wherein R12, R13, R14 and R15 have the significance given earlier, e.g. 2,3-dimethyl-2,3-butanediol, and reacting the resulting 2-(bromo-or fluoro-lower alkyl)-1,3,2-dioxaborolane with dichloromethane in the presence of lithium diisopropylamine. The hydroboration can be carried out in a conventional manner, for example using phenylboronic acid at an elevated temperature, e.g. about 100xc2x0 C., in the absence of a solvent or using borane-dimethyl sulfide complex in the presence of cyclohexene in an inert organic solvent, e.g. dimethoxyethane, at about 0xc2x0 C. followed by treatment with trimethylamine N-oxide.
A substituted dioxoborolane of formula III in which Q represents a group of formula (a) can also be synthesised on a solid phase peptide synthesis resin. For example, a 4-methylbenzhydryl resin can be reacted with a dioxoborolanyl-valeric acid represented by the general formula 
wherein R1, R2, R12, R14, R15 and Q1 have the significance given earlier, and the product can be converted into the required resin-bonded starting material by successive deprotection and coupling with a protected amino acid.
Compounds of formula IX can be conveniently prepared by reacting a tert-butyl 6,7-dihydroxy-3,6,7-tri(lower alkyl)-6-octenoate with dichloromethyl diisopropoxyborane, condensing the resulting compound represented by the general formula 
wherein R12, R14 and R15 have the significance given earlier, with a compound of formula R1MgHal, wherein R1 has the significance given earlier and Hal represents halogen, preferably bromine, under the conditions of a Grignard reaction, reacting the resulting compound represented by the general formula 
wherein R1, R12, R14 and R15 have the significance given earlier, with an alkali metal bis[tri(lower alkyl)silyl]amide, condensing the resulting compound represented by the general formula 
wherein R1, R12, R14 and R15 have the significance given earlier, with a protected amino acid represented by the general formula
Q2HNxe2x80x94CH(R2)xe2x80x94COOHxe2x80x83xe2x80x83(XIII)
wherein R2 has the significance given earlier and Q2 represents Fmoc, and de-esterifying the resulting compound represented by the general formula 
wherein R1, R2, R12, R14, R15 and Q2 have the significance given earlier.
As mentioned earlier, the compounds of formula I and salts of acidic compounds of formula I with bases are inhibitors of proteases of viral origin. The activity against one such protease, namely HCV protease, can be demonstrated using the following assay:
Construction of Plasmid for the Expression of MBP-NS3xe2x80x3Gly 12-NS4A Enzyme in E. coli 
The nucleotide sequence of this expression plasmid is given in SEQ ID NO:1 appended hereto and the amino acid sequence of its expression product is given in SEQ ID NO:2 appended hereto. It is based on the pMAL(copyright)-c2 vector supplied by New England Biolabs, Inc. (32 Tozer Rd., Beverly, Mass., USA). The principle of the construction was to create an in-frame fusion of the maltose binding protein (MBP) gene supplied by the pMAL-c2 vector, and sequences of the HCV genome necessary for NS3 proteinase activity. These HCV sequences were inserted between the EcoRI and HindIII sites of the pMAL-c2 polylinker (positions 2695 and 3556 respectively of the sequence given in SEQ ID NO:1).
HCV sequences were derived from plasmids pDS 3348-4045 and pBFK 3348-6062, described by Bartenschlager et al, 1993 (Journal of Virology, 67, 3835-3844). Regions encompassing the NS3 proteinase domain (amino acids 1007-1219) and the NS4A domain (amino acids 1658-1711) were isolated and inserted into the pMAL-c2 vector using standard recombinant DNA techniques, including the PCR amplification of required sequences. Between the NS3 and NS4A domains, a linker region was constructed using synthetic oligonucleotides (positions 3343-3390; amino acids 606-621). The resulting plasmid was used to transform E. coli (strain MC1061) cells and expression of the MBP-NS3xe2x80x3Gly 12-NS4A enzyme was induced as described below.
Protein Expression and Purification
E. coli (strain MC1061) cells transformed with the foregoing plasmid were grown in Luria broth containing ampicillin (100 xcexcg/ml) at 37xc2x0 C. The cells were grown until an optical density of 0.5 at 600 nm had been reached and enzyme expression was then induced by adding 1 mM isopropylthiogalactoside and incubating at 37xc2x0 C. for a further 3 hours. The cells were harvested by centrifugation and stored at xe2x88x9280xc2x0 C.
A pellet from 4 of bacterial culture was resuspended in E.coli lysis buffer (20 mM Tris HCl, pH 7.5, containing 150 mM NaCl, 1 mM EDTA and 10 mM dithiothreitol) and cell lysis was achieved by two passages through a French Pressure cell. The clear supernatant obtained by centrifugation (18000 g, 30 minutes) was then applied to an amylose resin column (4xc3x971 cm) (New England Biolabs) which had been equilibrated with ice-cold 50 mM Tris HCl, pH 8.5, containing 200 mM NaCl, 1 mM dithiothreitol and 5% glycerol. The column was washed thoroughly with the equilibration buffer and bound protein was eluted using the equilibration buffer containing 10 mM maltose. Fractions of 1 ml were collected, with fractions containing the enzyme being pooled and stored at xe2x88x9280xc2x0 C. Enzyme concentration was assayed by the method of M. B. Bradford, Analytical Biochemistry, 1976, vol. 72, p.248.
Assay
Compounds of formula I (routinely prepared as stock solutions in DMSO) were assayed for their ability to inhibit the cleavage of a quenched fluorescence substrate [NS4A/B.F peptide (N-[4-[4-(dimethylamino)phenylazo]benzoyl]-L-xcex1-aspartyl-L-(xcex1-glutamyl-L-methionyl-L-xcex1-glutamyl-L-xcex1-glutamyl-L-cysteinyl-L-alanyl-L-seryl-L-histidyl-N5-[2-(5-sulpho-1-naphthylamino)ethyl]-L-glutamin-amide); Wilkinson et al, Society for General Microbiology Meeting, University of Warwick, England, Mar. 28, 1996] based on the NS4A/4B cleavage site by enzyme MBP-NS3{acute over (ii)}Gly 12-NS4A in microtitre plates as follows:
The enzyme (0.4-0.6 xcexcg) was added to a mixture (200 xcexcl final volume) containing 50 mM Tris HCl, pH 8.5, with 1 mM NaCl, 0.1 mM EDTA, 1 mM dithiothreitol, 0.1% Triton X-100, 10 xcexcM NS4A/B.F peptide and the test compound of formula I prepared as a stock solution in DMSO and added to give a 10% final concentration of DMSO. The resulting mixture was incubated at room temperature for 60 minutes and the reaction was terminated by the addition of 100 xcexcl of 2M sodium dihydrogen orthophosphate. The progress of the reaction was evaluated with a Millipore Cytofluor 2350 using an excitation wavelenth of 360 nm and an emission wavelength of 530 nm. The reduction in fluorescence in the presence of the inhibitor was measured, and was plotted against inhibitor concentration. The inhibitor concentration which caused 50% reduction (IC50) was calculated by manual graph analysis.
The results obtained in the foregoing assay with representative compounds of formula I are compiled in the following Table:
A= 2(RS)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-L-xcex1-aspartyl-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-O-benzyl-L-tyrosyl]amino]-4,4,4-trifluorobutyraldehyde.
B= 2(RS)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-L-xcex1-aspartyl-O-benzyl-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde.
C= 2(RS)-[[N-[N-[N-[N2-(N-Acetyl-L-tyrosyl)-N6-nitro-L-arginyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde.
D= 2(RS)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-L-cysteinyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde.
E= 1(RS)-[[N-[N-[N-[N-[N-(4-Acetamidobutyryl)-L-xcex1-aspartyl-L-xcex1-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]propylboronic acid (SEQ ID NO:23).
F= 2(RS)-[[N-[N-[N-[N-[N-(9-Hydroxy-9-fluorenyl)carbonyl]-L-seryl]-O-benzyl-D-seryl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]-4,4,4-trifluorobutyraldehyde.
The compounds of formula I and salts of acidic compounds of formula I with bases can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered enterally such as orally in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, e.g. in the form of nasal sprays, or rectally, e.g. in the form of suppositories. They may, however, also be administered parenterally, e.g. in the form of injectable solutions.
The compounds of formula I and their aforementioned salts can be processed with pharmaceutically inert, organic or inorganic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a salt of an acidic compound of formula I with a base in association with a compatible pharmaceutical carrier are also within the scope of the present invention, as is a process for the production of such medicaments which comprises bringing one or more of these compounds or salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with a compatible pharmaceutical carrier.
As mentioned earlier, the compounds of formula I and salts of acidic compounds of formula I with bases can be used in accordance with the invention as therapeutically active substances, especially as antiviral agents. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of administration to adults a convenient daily dosage should be about 3 mg to about 3 g, preferably about 10 mg to 1 g. The daily dosage may be administered as a single dose or in divided doses and, in addition, the upper dosage limit referred to earlier may be exceeded when this is found to be indicated.
Finally, the use of compounds of formula I and salts of acidic compounds of formula I with bases for the production of medicaments, especially of antiviral medicaments, is also within the scope of the invention.